N-terminal acetylation modulates Bax targeting to mitochondria

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• The pro-apoptotic Bax protein initiates mitochondrial permeabilization during apoptosis.
• Bax activity is regulated by post-translational modifications like phosphorylation and S-palmitoylation.
• The role of other protein modifications, such as N-terminal acetylation, in Bax regulation is largely unexplored.

Purpose of the Study:

• To investigate the involvement of N-terminal acetylation by yeast N-acetyltransferase B (yNatB) in regulating human Bax function.
• To determine the impact of N-terminal acetylation on Bax conformation, localization, and apoptotic activity.

Main Methods:

• Heterologous expression of human Bax in yeast.
• Analysis of Bax localization and conformation in yeast and Mouse Embryonic Fibroblast (MEF) cells with altered NatB activity.
• Assessment of cytochrome c release as an indicator of apoptosis.

Main Results:

• Human Bax undergoes N-terminal acetylation mediated by yNaa20p (yNatB).
• N-terminal acetylation is essential for maintaining Bax in an inactive cytosolic conformation in both yeast and MEF cells.
• Loss of yNatB function leads to Bax accumulation in mitochondria, but without significant cytochrome c release, indicating incomplete activation.

Conclusions:

• Bax N-terminal acetylation by the NatB complex is a critical regulatory step.
• This modification plays a key role in controlling Bax mitochondrial targeting and maintaining its inactive state.
• Further steps are required for the full activation of Bax following its mitochondrial recruitment.